Kevin Shannon, MD. Photo by Cindy Chew2015-09-08 20:42:12.33818shannon_kevin.jpg421http://ti.ucsf.edu/files/f61sVa/shannon_kevin.jpg/icon.gif1335main267http://ti.ucsf.edu/files/f61sVa/shannon_kevin.jpg40037763http://ti.ucsf.edu/files/f61sVa/shannon_kevin.jpg/main.jpg85http://ti.ucsf.edu/files/f61sVa/shannon_kevin.jpg/thumb.jpg128image6301335http://cancer.ucsf.edu/news/2015/09/08/childhood-cancer-research-at-ucsf-to-transcend-tissue-types-with-innovative-grant.6756/ics/2015/09/08/childhood-cancer-research-at-ucsf-to-transcend-tissue-types-with-innovative-grant.6756/childhood-cancer-research-at-ucsf-to-transcend-tissue-types-with-innovative-grant.6756.ics6756left11840959/8/20152015-09-08 15:33:003:33 pmleft1211Unique $10 Million SPORE Award Builds on Two Decades of ‘Research Excellence’Unique $10 Million SPORE Award Builds on Two Decades of ‘Research Excellence’<p>
Researchers at UC San Francisco are leading a five-year, $10 million research project dedicated to pediatric cancer, funded by the first grant of its kind to focus on a molecular pathway that underlies many cancers rather than on a cancer in a particular organ or tissue in the body.</p>
Researchers at UC San Francisco are leading a five-year, $10 million research project dedicated to pediatric cancer, funded by the first grant of its kind to focus on a molecular pathway that underlies many cancers rather than on a cancer in a particular organ or tissue in the body. 51041525DHART SPOREdhart-spore1711526Jennifer Grandisjennifer-grandis1741063Kevin Shannonkevin-shannon173487Membershipmembership17391064Mignon Lohmignon-loh177935Pediatric Malignanciespediatric-malignancies17161527Scott Koganscott-kogan1711528SPOREspore1719/8/2015 3:33 pmUS/EasternChildhood Cancer Research at UCSF to Transcend Tissue Types With Innovative GrantChildhood Cancer Research at UCSF to Transcend Tissue Types With Innovative Grantchildhood-cancer-research-at-ucsf-to-transcend-tissue-types-with-innovative-grant.6756/2015/09/08/childhood-cancer-research-at-ucsf-to-transcend-tissue-types-with-innovative-grant.675667542016-09-26 19:01:39.091744-05publicUCSF.eduhttp://www.ucsf.edu/news/2015/09/131511/rare-melanoma-carries-unprecedented-burden-mutationsarticle13http://ti.ucsf.edu/element/auje3xj/counter/67542015-09-08 14:14:00-05<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
A rare, deadly form of skin cancer known as desmoplasmic melanoma (DM) may possess the highest burden of gene mutations of any cancer, suggesting that immunotherapy may be a promising approach for treatment, according to an international team led by UC San Francisco scientists. One of these mutations, never before observed in any cancer, may shield nascent DM tumors from destruction by the immune system and allow further mutations to develop.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;The focus of our lab has been to show that there&#39;s not just one &lsquo;melanoma&rsquo; but many different types,&rdquo; said senior author&nbsp;<a href="http://profiles.ucsf.edu/boris.bastian" style="box-sizing: border-box; outline: none; text-decoration: none; background-color: transparent; color: rgb(0, 124, 190); transition: color 0.15s; -webkit-transition: color 0.15s; background-position: initial initial; background-repeat: initial initial;" target="_blank">Boris Bastian</a>, MD, PhD, the Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research at UCSF. &ldquo;We&#39;ve already discovered genetic profiles that let us begin to separate them into groups and study them individually. But this is one type that has so far been left behind.&rdquo;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Unlike many melanomas which grow rapidly and appear as dark brown discolorations of the skin, DM is unusual in that it develops slowly and forms unpigmented scar-like bumps, occasionally accompanied by tingling sensations as the cancer grows into nerves. Its unusual appearance leads to delayed or incorrect diagnoses, which can be deadly, as the cancer tends to metastasize directly to the lung.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;Because these tumors are not pigmented, people often don&rsquo;t notice them until they&rsquo;re quite large,&rdquo; said lead author A. Hunter Shain, PhD, a postdoctoral fellow in Bastian&rsquo;s lab. &ldquo;And then it might be too late.&rdquo;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
DM accounts for four percent of melanomas, but until now its genetic basis was unknown, partly because it has been difficult for researchers to assemble a sufficient number of biopsy specimens to study. In previous research based on small numbers of specimens, scientists had looked for the mutations associated with more common forms of melanoma, but had found no leads, said Bastian, who is a member of the UCSF Helen Diller Family Comprehensive Cancer Center.&nbsp;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
As a result, Shain said, &ldquo;though DM is a very deadly form of melanoma, virtually nothing&#39;s known about it.&rdquo;</p>
<h5 style="box-sizing: border-box; font-size: 15px; line-height: 2.22222em; margin-top: 1.11111em; margin-bottom: 1.11111em; font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif; color: rgb(51, 51, 51); letter-spacing: 0.47999998927116394px;">
Sequencing Tumors Letter by Letter</h5>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
In the new study the researchers obtained 62 DM samples from UCSF, the Memorial Sloan Kettering Cancer Center in New York, and the Melanoma Institute Australia in Sydney, and performed next-generation, whole genome and exome sequencing, parsing the coding regions of the tumors&rsquo; genetic code &ldquo;letter by letter&rdquo; to identify common mutations between the samples.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
In line with its atypical clinical presentation, DM appears to be a genetic oddball among melanomas. The researchers detected few of the mutations commonly seen in other melanoma types, but instead identified mutations of pathways frequently implicated in other cancers for which some targeted therapies already exist.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Two other findings suggested an intriguing portrait of how DM develops, and how it might be treated.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
First was the discovery that DM tumors carry a surprisingly high number of mutations. Most solid tumors carry about two mutations per million base pairs, the genetic &ldquo;letters&rdquo; that make up genomes. More common melanomas, which often are caused by exposure to the ultraviolet component of sunlight, have more mutations: about 15 per million base pairs. In the current study, however, DM tumors carried about 62 mutations per million base pairs.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;This is the highest number of mutations we&rsquo;ve ever seen in an untreated tumor without any apparent defect in DNA repair,&rdquo; Bastian said.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
A second key finding was that one of the most common DM mutations, never before seen in cancer cells, occurred in a promoter region that regulates expression of the&nbsp;<em style="box-sizing: border-box;">NFKBIE</em>&nbsp;gene, which plays an important role in turning down immune responses. &nbsp;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;This is the first time this gene has popped up in any cancer,&rdquo; Bastian said. &ldquo;What&rsquo;s more, it&rsquo;s rare among known cancer mutations in that it resides in the regulatory &lsquo;dark matter&rsquo; of the genome, and not within the part of a gene that codes for a protein. Regulatory mutations like this routinely escape all but the most comprehensive genomic analysis.&rdquo;</p>
<h5 style="box-sizing: border-box; font-size: 15px; line-height: 2.22222em; margin-top: 1.11111em; margin-bottom: 1.11111em; font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif; color: rgb(51, 51, 51); letter-spacing: 0.47999998927116394px;">
Potential for Immune Therapy</h5>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Many researchers believe that cancers with high numbers of mutations are quickly detected and destroyed by circulating immune cells before they spiral out of control. However, the mutated&nbsp;<em style="box-sizing: border-box;">NFKBIE</em>&nbsp;promoter may allow affected cells to fly under the radar of the body&rsquo;s immune surveillance long enough to accumulate the numerous other mutations that eventually drive the cells to a cancerous state, Bastian speculated.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;It may be like a cloak of invisibility for the cancer cells,&rdquo; he said.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&nbsp;</p>
Nicholas Weiler25

"Skin Tumors-045" by LWozniak&KWZielinski - Own work. Licensed under CC BY-SA 3.0 via Commons.2015-09-08 14:31:32.356277Skin_Tumors045.jpg300http://ti.ucsf.edu/files/cUFFyE/Skin_Tumors045.jpg/icon.gif1333main1024http://ti.ucsf.edu/files/cUFFyE/Skin_Tumors045.jpg1280125322http://ti.ucsf.edu/files/cUFFyE/Skin_Tumors045.jpg/main.jpg128http://ti.ucsf.edu/files/cUFFyE/Skin_Tumors045.jpg/thumb.jpg128image3501333http://cancer.ucsf.edu/news/2015/09/07/rare-melanoma-carries-unprecedented-burden-of-mutations.6754/ics/2015/09/07/rare-melanoma-carries-unprecedented-burden-of-mutations.6754/rare-melanoma-carries-unprecedented-burden-of-mutations.6754.ics6754left11840969/7/20152015-09-07 12:11:0012:11 pmleft811<p>
A rare, deadly form of skin cancer known as desmoplasmic melanoma (DM) may possess the highest burden of gene mutations of any cancer, suggesting that immunotherapy may be a promising approach for treatment, according to an international team led by UC San Francisco scientists.</p>
A rare, deadly form of skin cancer known as desmoplasmic melanoma (DM) may possess the highest burden of gene mutations of any cancer, suggesting that immunotherapy may be a promising approach for treatment, according to an international team led by UC San Francisco scientists. 51021523A. Hunter Shaina.-hunter-shain1711111Boris Bastianboris-bastian174328Geneticsgenetics1719956Immunotherapyimmunotherapy1716600Melanomamelanoma1761524Raymond Choraymond-cho1719/7/2015 12:11 pmUS/EasternRare Melanoma Carries Unprecedented Burden of MutationsRare Melanoma Carries Unprecedented Burden of Mutationsrare-melanoma-carries-unprecedented-burden-of-mutations.6754/2015/09/07/rare-melanoma-carries-unprecedented-burden-of-mutations.675467502015-09-23 18:31:52.174555-05publicUCSF.eduhttp://www.ucsf.edu/news/2015/09/131421/genes-may-make-radiation-riskier-pediatric-cancer-patientsarticle13http://ti.ucsf.edu/element/auje3xj/counter/67502015-09-04 12:48:32-05<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
Genetic vulnerabilities associated with childhood cancers may make children undergoing radiation therapy more susceptible than adults to secondary cancers, according to novel insights from researchers at UC San Francisco.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
Malignancies caused by radiation therapy are a major cause of mortality in childhood cancer patients and affect approximately 10 percent of long-term survivors, depending on diagnosis and prognosis. These secondary malignancies arise from DNA injury following radiation therapy and can be aggressive and challenging to treat.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
While they can also occur in adults, experts are recognizing that they are more common in children.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
In the study published Sept. 3,&nbsp;in&nbsp;<em style="box-sizing: border-box;">Cell Reports</em>, a team of international scientists, headed by senior author<a href="http://cancer.ucsf.edu/people/profiles/nakamura_jean.3525" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">Jean Nakamura</a>, MD, of UCSF, conducted an analysis of tumors in mice that were caused by both exposure to radiation and genetic mutations.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
The researchers compared the prevalence of cancer in normal mice to those with a mutation in the Nf1 gene, which encodes a tumor-suppressing protein called neurofibromin. Children born with mutations in this gene have neurofibromatosis 1, a condition that predisposes them to tumors. In order to parallel the effects of radiation therapy on pediatric patients, young mice underwent focused radiation targeted to the abdominal wall. The dosing was similar to that received by patients.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
After radiation the Nf1 mice harbored more tumors and had shorter lifespans than the normal mice.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
&ldquo;Comparing malignancies from two different genetic backgrounds helps us understand which genetic alterations are attributable to radiation and which genetic alterations are attributable to the germline mutations, those mutations present at birth,&rdquo; said Nakamura, associate professor of radiation oncology in the UCSF School of Medicine and a physician at UCSF Benioff Children&rsquo;s Hospital San Francisco.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
The scientists sequenced malignancies from 19 mice, of which 15 tumors occurred in Nf1 mice and seven in normal mice, and identified common mutational signatures, irrespective of tumor type and genetic background.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
The researchers looked at sarcomas, tumors usually arising from muscle or bone that are common secondary malignancies, and found that those of the Nf1 mice had fewer changes in DNA sequence than the normal mice. They also found that the cancers of the Nf1 mice were significantly more likely to have lost large segments of individual chromosomes compared to the normal mice. These findings indicate that germline mutations in Nf1 influence the numbers and types of genetic alterations found in tumors. Nakamura and her colleagues now are analyzing radiation-induced malignancies from pediatric patients for the mutation patterns they discovered in the mice.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em;">
&ldquo;If we can identify whether germline mutations are contributing to cancer development in pediatric patients, we have the potential to personalize cancer therapy and health management approaches to help these patients enjoy long-term health,&rdquo; said Nakamura. &ldquo;Since individual patients have individual genetic profiles and different radiation exposure, we might be able to tailor medical care to integrate this information, rather than offering the same treatment to all children with the same diagnosis.&rdquo;</p>
Suzanne Leigh25

This color washed CT scan shows graduated doses of radiation extending outwards from a brain tumor. The red central area is the high-dose region shaped to match tumor dimensions.

This color washed CT ...2015-09-04 12:48:04.48183graduateddosesofradiationctscanofbrain01.png630http://ti.ucsf.edu/files/lxjgru/graduateddosesofradiationctscanofbrain01.png/icon.gif1331main343http://ti.ucsf.edu/files/lxjgru/graduateddosesofradiationctscanofbrain01.png2701020523http://ti.ucsf.edu/files/lxjgru/graduateddosesofradiationctscanofbrain01.png/main.png128http://ti.ucsf.edu/files/lxjgru/graduateddosesofradiationctscanofbrain01.png/thumb.png128CT Scanimage4961331http://cancer.ucsf.edu/news/2015/09/03/genetic-makeup-may-make-radiation-riskier-for-pediatric-cancer-patients.6750/ics/2015/09/03/genetic-makeup-may-make-radiation-riskier-for-pediatric-cancer-patients.6750/genetic-makeup-may-make-radiation-riskier-for-pediatric-cancer-patients.6750.ics6750left11461249/3/20152015-09-03 16:00:004:00 pmleft711Study Points to Potential for Personalized TherapiesStudy Points to Potential for Personalized Therapies<p>
Genetic vulnerabilities associated with childhood cancers may make children undergoing radiation therapy more susceptible than adults to secondary cancers, according to novel insights from researchers at UC San Francisco.</p>
Genetic vulnerabilities associated with childhood cancers may make children undergoing radiation therapy more susceptible than adults to secondary cancers, according to novel insights from researchers at UC San Francisco. 50981521Jean Nakamurajean-nakamura171935Pediatric Malignanciespediatric-malignancies1716807Pediatric Malignancies Programpediatric-malignancies-program1715532radiationradiation1729/3/2015 4:00 pmUS/EasternGenetic Makeup May Make Radiation Riskier for Pediatric Cancer PatientsGenetic Makeup May Make Radiation Riskier for Pediatric Cancer Patientsgenetic-makeup-may-make-radiation-riskier-for-pediatric-cancer-patients.6750/2015/09/03/genetic-makeup-may-make-radiation-riskier-for-pediatric-cancer-patients.675067462015-09-08 20:33:07.091417-05publicUCSF.eduhttp://www.ucsf.edu/news/2015/09/131441/drug-fungal-infections-lung-transplant-recipients-increases-risk-skin-cancerarticle13http://ti.ucsf.edu/element/auje3xj/counter/67462015-09-03 11:34:13-05<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Voriconazole, a prescription drug commonly used to treat fungal infections in lung transplant recipients, significantly increases the risk for skin cancer and even death, according to a new study by UC San Francisco researchers. The team recommends physicians consider patient-specific factors that could modify the drug&rsquo;s risks and benefits, when providing care.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Their study appears online Sept. 3, in the&nbsp;<em style="box-sizing: border-box;">American Journal of Transplantation</em>.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;It is important for physicians to be aware of the impact of voriconazole on these outcomes,&rdquo; said senior author&nbsp;<a href="http://cancer.ucsf.edu/people/profiles/arron_sarah.3338" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">Sarah Arron</a>, MD, PhD, associate professor of dermatology and director of the&nbsp;<a href="http://www.ucsfhealth.org/clinics/high_risk_skin_cancer/" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">UCSF High Risk Skin Cancer Clinic</a>. &ldquo;We recommend that all providers counsel lung transplant recipients on skin cancer risk and photoprotection in addition to scheduling routine skin cancer screening with a trained dermatologist after transplantation. Lung transplant programs should also consider patient-specific risk factors when deciding on the type, dose and duration of antifungal prophylaxis regimens.&rdquo;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Skin cancer is the most common malignancy following solid organ transplants, primarily due to immunosuppression, with recipients experiencing a greater than 65-fold increased risk of developing cutaneous squamous cell carcinoma (SCC) compared to the general population. These carcinomas are aggressive and can lead to numerous lesions, resulting in multiple debilitating surgeries and increased risk of death.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Lung transplant recipients are particularly susceptible to SCC due to older age at transplant and more intensive immunosuppression. They also have high rates of fungal infections after transplant, which can result in significant morbidity and mortality.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
First approved in 2002, voriconazole is used to prevent and treat invasive fungal infections like those caused by the&nbsp;<em style="box-sizing: border-box;">Aspergillus</em>&nbsp;fungi, especially in patients with compromised immune systems such as following a lung or other organ transplant. The&nbsp;<em style="box-sizing: border-box;">Aspergillus</em>&nbsp;fungi can cause aspergillosis, a variety of diseases often occurring in people with healthy immune systems but having an underlying illness such as tuberculosis or chronic obstructive pulmonary disease (COPD).</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
However, SCC is a serious side effect of voriconazole, which has no clear guidelines for prophylaxis regimens despite its widespread use.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
In their study, Arron and her colleagues evaluated all UCSF single-lung, double-lung or heart-lung transplant recipients receiving a transplant between October 1991 and December 2012. These 455 individuals were analyzed for voriconazole exposure and its impact on SCC,&nbsp;<em style="box-sizing: border-box;">Aspergillus</em>&nbsp;colonization, invasive aspergillosis and all-cause mortality.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
The researchers found that voriconazole exposure resulted in a 73 percent greater risk for SCC, with each additional 30-day exposure increasing the risk by 3 percent.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Further, the drug significantly reduced the risk of&nbsp;<em style="box-sizing: border-box;">Aspergillus</em>&nbsp;colonization, especially in the first year after transplant, but not aspergillosis. It also reduced all-cause mortality among those transplant recipients who developed&nbsp;<em style="box-sizing: border-box;">Aspergillus</em>&nbsp;colonization but had no significant impact on those without colonization.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;Among lung transplant recipients with risk factors for SCC, including those with older age, male sex and white race or those in whom prolonged voriconazole administration may not have clear benefit, transplant physicians should consider limiting exposure to high doses of voriconazole or using alternative pharmacologic options that do not pose an increased risk for SCC,&rdquo; said lead author Matthew Mansh, MD, who did the work as a doctoral student at Stanford University that included a research year in the UCSF Department of Dermatology.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Other UCSF contributors to the&nbsp;<em style="box-sizing: border-box;">American Journal of Transplantation</em>&nbsp;study were Max Binstock, dermatology research coordinator; Kiyanna Williams, dermatology medical student; Farhaan Hafeez, dermatology medical student; Julie Kim, dermatology medical student;&nbsp;<a href="http://cancer.ucsf.edu/people/profiles/glidden_david.3302" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">David Glidden</a>, PhD, professor of epidemiology and biostatistics; Rebecca Boettger, PharmD, pharmacist;&nbsp; Steven Hays,&nbsp;MD, associate professor of medicine and lung transplant program medical director; <a href="http://cancer.ucsf.edu/people/profiles/kukreja_jasleen.3435" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">Jasleen Kukreja</a>, MD, MPH, associate professor of surgery and surgical director of the lung transplant program;&nbsp;<a href="http://cancer.ucsf.edu/people/profiles/golden_jeffrey.3510" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">Jeffrey Golden</a>, MD, professor of medicine and associate medical director of lung transplantation;&nbsp; Peter Chin-Hong, MD, professor of medicine; and&nbsp; Jonathan Singer, MD, assistant professor of medicine. Maryam Asgari, MD, of Kaiser Permanente Northern California, also contributed.</p>
Scott Maier252015-09-03 11:41:58.06735Voriconazole_structure.gif507http://ti.ucsf.edu/files/jlXt4Y/Voriconazole_structure.gif/icon.gif1329main346http://ti.ucsf.edu/files/jlXt4Y/Voriconazole_structure.gif43020947http://ti.ucsf.edu/files/jlXt4Y/Voriconazole_structure.gif/main.gif128http://ti.ucsf.edu/files/jlXt4Y/Voriconazole_structure.gif/thumb.gif128Voriconazoleimage6301329http://cancer.ucsf.edu/news/2015/09/03/drug-for-fungal-infections-in-lung-transplant-recipients-increases-risk-for-skin-cancer-even-death.6746/ics/2015/09/03/drug-for-fungal-infections-in-lung-transplant-recipients-increases-risk-for-skin-cancer-even-death.6746/drug-for-fungal-infections-in-lung-transplant-recipients-increases-risk-for-skin-cancer-even-death.6746.ics6746left11452089/3/20152015-09-03 09:25:009:25 amleft611UCSF Researchers Recommend Physicians Consider Patient-Specific Factors When Using VoriconazoleUCSF Researchers Recommend Physicians Consider Patient-Specific Factors When Using Voriconazole<p>
Voriconazole, a prescription drug commonly used to treat fungal infections in lung transplant recipients, significantly increases the risk for skin cancer and even death, according to a new study by UC San Francisco researchers. The team recommends physicians consider patient-specific factors that could modify the drug&rsquo;s risks and benefits, when providing care.</p>
Voriconazole, a prescription drug commonly used to treat fungal infections in lung transplant recipients, significantly increases the risk for skin cancer and even death, according to a new study by UC San Francisco researchers. The team recommends physicians consider patient-specific factors that could modify the drug&rsquo;s risks and benefits, when providing care. 50941515David Gliddendavid-glidden1711516Jasleen Kukrejajasleen-kukreja1711517Jeffrey Goldenjeffrey-golden171192Researchresearch17201518Sarah Arronsarah-arron171455skin cancerskin-cancer1771519Voriconazolevoriconazole1719/3/2015 9:25 amUS/EasternDrug for Fungal Infections in Lung Transplant Recipients Increases Risk for Skin Cancer, Even DeathDrug for Fungal Infections in Lung Transplant Recipients Increases Risk for Skin Cancer, Even Deathdrug-for-fungal-infections-in-lung-transplant-recipients-increases-risk-for-skin-cancer-even-death.6746/2015/09/03/drug-for-fungal-infections-in-lung-transplant-recipients-increases-risk-for-skin-cancer-even-death.674667402015-09-03 12:40:49.715919-05publicUCSF.eduhttp://www.ucsf.edu/news/2015/08/131431/dna-guided-3-d-printing-human-tissue-unveiledarticle13http://ti.ucsf.edu/element/auje3xj/counter/67402015-09-01 21:40:00-05<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
A UCSF-led team has developed a technique to build tiny models of human tissues, called organoids, more precisely than ever before using a process that turns human cells into a biological equivalent of LEGO bricks. These mini-tissues in a dish can be used to study how particular structural features of tissue affect normal growth or go awry in cancer. They could be used for therapeutic drug screening and to help teach researchers how to grow whole human organs.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
The new technique &mdash; called DNA Programmed Assembly of Cells (DPAC) and reported in the journal&nbsp;<em style="box-sizing: border-box;"><a href="http://dx.doi.org/10.1038/nmeth.3553" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;">Nature Methods</a>&nbsp;</em>on Aug. 31&nbsp;&mdash; allows researchers to create arrays of thousands of custom-designed organoids, such as models of human mammary glands containing several hundred cells each, which can be built in a matter of hours.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
There are few limits to the tissues this technology can mimic, said&nbsp;<a href="http://cancer.ucsf.edu/people/profiles/gartner_zev.6747" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">Zev Gartner</a>, PhD, the paper&rsquo;s senior author and an associate professor of pharmaceutical chemistry at UCSF. &ldquo;We can take any cell type we want and program just where it goes. We can precisely control who&rsquo;s talking to whom and who&rsquo;s touching whom at the earliest stages. The cells then follow these initially programmed spatial cues to interact, move around, and develop into tissues over time.&rdquo;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;One potential application,&rdquo; Gartner said, &ldquo;would be that within the next couple of years, we could be taking samples of different components of a cancer patient&rsquo;s mammary gland and building a model of their tissue to use as a personalized drug screening platform. Another is to use the rules of tissue growth we learn with these models to one day grow complete organs.&rdquo;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
Our bodies are made of more than 10 trillion cells of hundreds of different kinds, each of which plays its unique role in keeping us alive and healthy. The way these cells organize themselves structurally in different organ systems helps them coordinate their amazingly diverse behaviors and functions, keeping the whole biological machine running smoothly. But in diseases such as breast cancer, the breakdown of this order has been associated with the rapid growth and spread of tumors.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;Cells aren&rsquo;t lonely little automatons,&rdquo; Gartner said. &ldquo;They communicate through networks to make group decisions. As in any complex organization, you really need to get the group&rsquo;s structure right to be successful, as many failed corporations have discovered. In the context of human tissues, when organization fails, it sets the stage for cancer.&rdquo;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
But studying how the cells of complex tissues like the mammary gland self-organize, make decisions as groups, and break down in disease has been a challenge to researchers. The living organism is often too complex to identify the specific causes of a particular cellular behavior. On the other hand, cells in a dish lack the critical element of realistic 3-D structure.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
&ldquo;This technique lets us produce simple components of tissue in a dish that we can easily study and manipulate,&rdquo; said&nbsp;<a href="http://profiles.ucsf.edu/michael.todhunter" style="box-sizing: border-box; outline: none; text-decoration: none; color: rgb(0, 124, 190); transition-property: color; -webkit-transition-property: color; transition-duration: 0.15s; -webkit-transition-duration: 0.15s; background: transparent;" target="_blank">Michael Todhunter</a>, PhD, who led the new study with Noel Jee, PhD, when both were graduate students in the Gartner research group. &ldquo;It lets us ask questions about complex human tissues without needing to do experiments on humans.&rdquo;</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
To specify the 3-D structure of their organoids, Gartner&rsquo;s team makes use of a familiar molecule: DNA. The researchers incubate cells with tiny snippets of single-stranded DNA engineered to slip into the cells&rsquo; outer membranes, covering each cell like the hairs on a tennis ball. These DNA strands act both as a sort of molecular Velcro and as a bar code that specifies where each cell belongs within the organoid. When two cells incubated with complementary DNA strands come in contact, they stick fast. If the DNA sequences don&rsquo;t match, the cells float on by. Cells can be incubated with several sets of DNA bar codes to specify multiple allowable partners.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
To turn these cellular LEGOs into arrays of organoids that can be used for research, Gartner&rsquo;s team lays down the cells in layers, with multiple sets of cells designed to stick to particular partners. Not only does this let them build up complex tissue components like the mammary gland, but also to experiment with specifically adding in a single cell with a known cancer mutation to different parts of the organoid to observe its effects.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
To demonstrate the precision of the technique and its ability to generalize to many different human tissue types, the research team created several proof-of-principle organoid arrays mimicking human tissues such as branching vasculature and mammary glands.</p>
<p style="box-sizing: border-box; margin: 1em 0px; line-height: 22px; font-size: 15px; letter-spacing: 0.02em; color: rgb(53, 58, 63); font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;">
In one experiment, the researchers created arrays of mammary epithelial cells and asked how adding one or more cells expressing low levels of the cancer gene&nbsp;<em style="box-sizing: border-box;">RasG12V</em>&nbsp;affected the cells around them. They found that normal cells grow faster when in an organoid with cells expressing&nbsp;<em style="box-sizing: border-box;">RasG12V&nbsp;</em>at low levels, but required more than one mutant cell to kick-start this abnormal growth. They also found that placing cells with low&nbsp;<em style="box-sizing: border-box;">RasG12V</em>expression at the end of a tube of normal cells allowed the mutant cells to branch and grow, drawing normal cells behind them like a bud at the tip of a growing tree branch.</p>
Nicholas Weiler25http://cancer.ucsf.edu/news/2015/09/01/dna-guided-3-d-printing-of-human-tissue-is-unveiled.6740/ics/2015/09/01/dna-guided-3-d-printing-of-human-tissue-is-unveiled.6740/dna-guided-3-d-printing-of-human-tissue-is-unveiled.6740.ics6740left11448309/1/20152015-09-01 19:33:007:33 pmleft811Technique Produces ‘Organoids’ Useful in Cancer Research, Drug ScreeningTechnique Produces ‘Organoids’ Useful in Cancer Research, Drug Screening<p>
A UCSF-led team has developed a technique to build tiny models of human tissues, called organoids, more precisely than ever before using a process that turns human cells into a biological equivalent of LEGO bricks.</p>
A UCSF-led team has developed a technique to build tiny models of human tissues, called organoids, more precisely than ever before using a process that turns human cells into a biological equivalent of LEGO bricks. 5088588Breast Oncologybreast-oncology1733665Cancer, Immunity, and Microenvironmentcancer-immunity-and-microenvironment1712985programmaticprogrammatic1717192Researchresearch17201520Zev Gartnerzev-gartner1739/1/2015 7:33 pmUS/EasternDNA-Guided 3-D Printing of Human Tissue is UnveiledDNA-Guided 3-D Printing of Human Tissue is Unveileddna-guided-3-d-printing-of-human-tissue-is-unveiled.6740/2015/09/01/dna-guided-3-d-printing-of-human-tissue-is-unveiled.674067202015-08-27 14:37:25.472265-05publicUCSF.eduhttp://www.ucsf.edu/news/2015/08/131401/mammary-gland-shaped-adaptive-immune-system-during-developmentarticle13http://ti.ucsf.edu/element/auje3xj/counter/67202015-08-27 11:10:10-05<p>
In experiments with mouse tissue, UC San Francisco researchers have discovered that the adaptive immune system, generally associated with fighting infections, plays an active role in guiding the normal development of mammary glands, the only organs--in female humans as well as mice--that develop predominately after birth, beginning at puberty.</p>
<p>
The scientists say the findings have implications not only for understanding normal organ development, but also for cancer and tissue-regeneration research, as well as in the highly active field of cancer immunotherapy, which seeks to develop drugs that prompt the adaptive immune system to attack tumor cells.</p>
<p>
&ldquo;It&rsquo;s essential that we pay attention to how normal development unfolds, because regeneration requires reigniting developmental processes, and cancer can be thought of as &lsquo;development gone wrong,&rsquo;&rdquo; said senior author <a href="http://cancer.ucsf.edu/people/profiles/werb_zena">Zena Werb, PhD</a>, professor and vice-chair of anatomy at UCSF and co-leader of the Cancer, Immunity and Microenvironment Program at the UCSF Helen Diller Family Comprehensive Cancer Center.</p>
<p>
Previous research has shown that the innate immune system, a suite of evolutionarily ancient, general-purpose defenses that is fully operational before birth, helps to orchestrate the development of several organs both pre- and postnatally. The adaptive immune system, which springs into action after birth to continually create customized antibodies over a lifetime to protect us against the pathogens we encounter, also is known to influence the development of immune system organs such as the thymus, spleen and lymph nodes.</p>
<p>
But the new discoveries, published online in <em>Developmental Cell</em> on Aug. 27, 2015, break new ground by demonstrating that the adaptive immune system can play a conducive role in the postnatal development of organs not directly involved in immunity, said first author Vicki Plaks, PhD, a postdoctoral fellow in the Werb laboratory who led the new research.</p>
<p>
The mouse mammary gland is an excellent model to study these processes &ndash; it develops &ldquo;from almost nothing to everything&rdquo; in about four weeks, said Plaks, and matures roughly in parallel with adaptive immunity &ndash; but the researchers said that the findings may also apply to the prostate gland, skin, and gut, all of which undergo postnatal structural changes.</p>
<p>
Mice have 10 mammary glands, which consist of a structure known as a fat pad that, at birth, contains a rudimentary stalk of cells called epithelial cells. At puberty, an explosive growth process known as &ldquo;ductal invasion&rdquo; takes place within each gland: epithelial cells rapidly and extensively proliferate throughout the fat pad in a complex branching pattern, forming a series of tubes that connect with a hollow space called the lumen, through which milk will eventually flow to the nipple.</p>
<p>
To observe these events close-up, the researchers created three-dimensional assemblages known as &ldquo;organoids&rdquo; that were embedded in a gel matrix and replicated the cellular interrelationships, including the resident immune-cell populations, of the mouse fat pad. Fluorescent labels of various colors were applied to each cell type, enabling the scientists to use microscopes to record movies over several days to capture the interactions of immune and epithelial cells during ductal invasion.</p>
<p>
The movies show that immune-system cells known as antigen-presenting cells (APCs) continually proliferate and survey the rapidly developing organoids, sending signals to nearby immune T cells called CD4+ cells. The CD4+ T cells, in turn, secrete a substance called interferon-gamma, which signals epithelial cells that they should cease their advancement. These repeated interactions between APCs and CD4+ T cells accompany the sculpting of the lumen and the branching of the tissue.</p>
<p>
By selectively depleting and introducing relevant immune cell populations, as well as knocking out genes affecting the function of APCs, CD4+ T cells, and interferon-gamma in successive organoids and in whole mammary glands, the researchers were able to confirm that each component of the system is necessary to assist ductal invasion, allowing the process to unfold in an orderly fashion.</p>
<p>
&ldquo;This work shows that the adaptive immune system does more than kill pathogens. I&rsquo;d speculate that while it&rsquo;s sitting there ready to mount a defense against infections, the adaptive immune system might perform other duties to maintain the health of the organism,&rdquo; said Plaks. &ldquo;Fine-tuning is needed for organs to develop adequately, and perhaps part of the immune system&rsquo;s role may be to control developmental processes in this very refined way.&rdquo;</p>
<p>
&nbsp;</p>
Pete Farley25